Biomedicines. 2025 Feb 22;13(3):558. doi: 10.3390/biomedicines13030558.

ABSTRACT

Background/Objectives: Patients suffering from rare diseases are particularly vulnerable to vitamin D deficiency. The role of vitamin D status in rare disease management remains insufficiently investigated and employed in routine clinical practice. Methods: This review analyses current data on vitamin D status in selected rare diseases of organs involved in vitamin D metabolism: skin (epidermolysis bullosa, morphea), liver (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis), kidney (Alport syndrome, Fabry disease), and cystic fibrosis as a model of a systemic rare disease. Additionally, this review critically examines potential drug-vitamin D interactions in the context of rare disease patient polypharmacy. Results: Evidence suggests that vitamin D deficiency is prevalent in rare disease patient populations, often at once exacerbating and being simultaneously exacerbated by the underlying condition. Vitamin D deficiency correlates with worse clinical outcomes and lower quality of life across the examined diseases. Immunoregulatory properties of vitamin D appear relevant for rare diseases with autoimmune components. Conclusions: An urgent need for developing disease-specific clinical practice guidelines, implementing routine vitamin D monitoring in rare disease patient care, and introducing tailored supplementation under the principles of precision medicine is emphasized.

PMID:40149535 | DOI:10.3390/biomedicines13030558

Antibiotics (Basel). 2025 Mar 18;14(3):317. doi: 10.3390/antibiotics14030317.

ABSTRACT

Background:Nocardia species are an emergent pathogen in people with CF (pwCF) or bronchiectasis. Their clinical role and management remain unclear, and their isolation is a challenge. In this paper, we describe four cases of Nocardia detection, in two pwCF and two patients with non-CF bronchiectasis or primary ciliary dyskinesia (PCD). Methods: We conducted a multicenter retrospective study, involving pwCF and non-CF people with bronchiectasis who presented with a Nocardia detection and were followed at three CF Italian centers (Florence, Verona, and Cerignola). Results:Nocardia detection was associated with clinical and radiological respiratory exacerbation and decline in lung function. In one CF patient, Nocardia was not detected in sputum cultures after starting Elexacaftor-Tezacaftor-Ivacaftor therapy. Conclusions: Managing Nocardia detection in patients with underlying lung diseases such as CF, PCD, or bronchiectasis presents significant challenges for clinicians.

PMID:40149127 | DOI:10.3390/antibiotics14030317

Antibiotics (Basel). 2025 Mar 14;14(3):302. doi: 10.3390/antibiotics14030302.

ABSTRACT

Pseudomonas aeruginosa is one of the leading causes of nosocomial respiratory tract infections, significantly affecting morbidity and mortality. It can persist in the lungs of patients with cystic fibrosis (CF) for extended periods because of its adaptive capacity. The main aim of this study was to determine the phenotypic and genotypic resistance to antibiotics of clinical isolates of P. aeruginosa that persist in patients with CF receiving long-term antimicrobial therapy. The study included nine strains of P. aeruginosa isolated from the sputum of patients with CF admitted to the hospital. Susceptibility to antibiotics was determined using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Whole-genome sequencing was performed for phylogeny, sequence typing, and to identify antibiotic-resistant genes. The study showed that during long-term persistence in the lungs of patients receiving antibacterial therapy, the restoration of susceptibility to antibiotics occurred in some cases. Multilocus sequence typing and phylogeny revealed six sequence types. Functional annotation identified 72 genes responsible for resistance to antibacterial and chemical substances, with either chromosomal or plasmid localisation.

PMID:40149112 | DOI:10.3390/antibiotics14030302

J Cyst Fibros. 2025 Mar 26:S1569-1993(25)00079-7. doi: 10.1016/j.jcf.2025.03.011. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a disease triggered by more than 2,100 variants in a single gene encoding for the CF Transmembrane Conductance Regulator (CFTR) protein, which is expressed in epithelial cells, where it functions an anion channel. A new era of high-throughput technologies ('omics') enabled the production and exploration of large CF-related datasets with unprecedented detail. However, this knowledge is scattered among different resources thus requiring a significant amount of time and training to collect and exploit. The objective of this work is to build a resource (CyFidb) that concentrates CF-related information in a single repository.

METHODS: This tool results from the intense manual curation of 407 scientific articles, including studies with CFTR variants in distinct conditions, drug treatments and cells/tissues.

RESULTS: CyFidb is divided into three levels of information: protein-protein interactions, gene expression and functional studies, from which it is possible to search and extract information.

CONCLUSIONS: CyFidb is an open-access resource (https://cyfidb.di.fc.ul.pt) designed to provide continuously updated, curated information on CFTR variants and their associated biological data.

PMID:40148144 | DOI:10.1016/j.jcf.2025.03.011

Respir Med. 2025 Mar 25:108056. doi: 10.1016/j.rmed.2025.108056. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis-related diabetes (CFRD) are known to have reduced exercise capacity (EC), which in turn is related to increased morbidity and mortality. The aim of this study was to examine whether dysglycaemia may independently influence exercise capacity in people with CF (pwCF).

METHODS: Results from clinically conducted cardiopulmonary exercise tests were analysed retrospectively in 139 pwCF alongside routine clinical data. Subjects were grouped according to glycaemic status; normal glucose tolerance (NGT; n=43) and dysglycaemia; impaired glucose tolerance (IGT; n=17) and CFRD (n=79). Anthropometric data was assessed using chi-squared tests. Regression models were developed using analysis of co-variance (ANCOVA) to evaluate predictors of exercise capacity and correlations between variable were assessed using the Pearson method.

RESULTS: Maximal oxygen uptake (VO2max) was reduced in the CFRD group compared to NGT and IGT (p<0.01), however this was dependent on higher FEV1% in the NGT and IGT groups (p<0.001) and significant differences were no longer present when FEV1 was accounted for. A higher proportion of those with dysglycaemia were ventilatory limited (NGT;42%, IGT; 72% & CFRD; 65%, p<0.05). Age, gender, BMI, intravenous antibiotic days and FEV1% were significant predictors of VO2max across all patients (adjusted R2=0.528, p<0.001). HbA1c is a small but significant predictor of VO2max in patients with dysglycaemia (p<0.05).

CONCLUSIONS: Adults with CFRD have reduced VO2max compared to NGT or IGT which is mediated by poorer lung function and higher overall disease burden. In individuals with CFRD, better glycaemic control is associated with a greater EC.

PMID:40147571 | DOI:10.1016/j.rmed.2025.108056

R I Med J (2013). 2025 Apr 1;108(4):26-31.

ABSTRACT

BACKGROUND: Novel therapies have increased life expectancy for people with cystic fibrosis (pwCF), shifting care to adult providers with limited CF experience. Hospitalizations expose trainees to CF care, but educational tools for managing CF exacerbations are scarce.

METHODS: A six-year longitudinal study assessed internal medicine resident physician trainees' (RPTs) experience managing hospitalized pwCF. A mixed-method survey of RPTs informed the creation of educational and workflow tools, including a video didactic and order set. A targeted knowledge assessment measured the effectiveness of these tools. Multidisciplinary team meetings also tracked challenges and outcomes.

RESULTS: Among 48 RPTs surveyed, 83% cared for pwCF during training. Most reported less comfort managing pwCF compared to diseases like chronic obstructive pulmonary disease (COPD). Immediately after implementing targeted educational tools, knowledge scores improved, particularly in CF-related diabetes management (38.4% correct pre vs 61.5% correct post, p=0.04).

CONCLUSION: Rare disease education requires focused assessments of learners' needs, sustained reinforcement, and adaptable tools to maintain effectiveness.

PMID:40146222

Tuberk Toraks. 2025 Mar;73(1):11-19. doi: 10.5578/tt.202501999.

ABSTRACT

INTRODUCTION: Early diagnosis with newborn screening programs and prolonged life expectancy with new treatment strategies have made cardiovascular disease (CVD) one of the important issues in cystic fibrosis (CF). In the early stages of CVD, it is difficult to recognize and follow-up increased arterial stiffness with conventional methods. Different measurement methods are needed. Therefore, in this study, we aimed to use arterial stiffness measurements in the follow-up of children with CF.

MATERIALS AND METHODS: This is a follow-up study examining the changes in arterial stiffness in children with CF by repeating hemodynamic measurements [augmentation index (AIx) and pulse wave velocity (PWV)]. We repeated hemodynamic measurements and CF-related CVD risk factors (Atherosclerosis risk factors: Fasting blood sugar, lipid profiles, and HbA1c) and systemic inflammation markers [C-reactive protein (CRP) and immunoglobulin G and pulmonary function tests] in children undergoing routine annual complication evaluation and examined changes during follow-up.

RESULT: Hemodynamic measurements could be repeated in 37 of 52 patients due to inclusion criteria. Mean age of the study group was 12 ± 4.5 years and 48.6% were female. There was a statistically significant increase in high density lipoprotein, HbA1c, and CRP and a decrease in low density lipoprotein and FEV1 at the follow-up. Heart rate, central blood pressure, augmented pressure, and PWV were similar. AIx, peripheral systolic blood pressure (SBP), and mean arterial pressure were increased significantly (p< 0.05). The increase in AIx was greater than expected for age and greater in female patients and in those with low body mass index, moderate-severe disease, and high CRP levels. Also, the change in AIx was positively correlated with changes in peripheral SBP and CRP.

CONCLUSIONS: This is the first study to evaluate the use of PWV and AIx in the follow-up of children with CF and showed that arterial stiffness measured with AIx increased at follow-up. The use of markers of arterial stiffness in CF from childhood onwards may enable early detection and monitoring of CVD risk and future prevention.

PMID:40145819 | DOI:10.5578/tt.202501999

Cochrane Database Syst Rev. 2025 Mar 27;3:CD016039. doi: 10.1002/14651858.CD016039.

ABSTRACT

RATIONALE: Cystic fibrosis (CF) is a common genetic condition in which progressive lung disease leads to morbidity and mortality. Non-tuberculous mycobacteria (NTM) are mycobacteria, other than those in the Mycobacterium tuberculosis complex, and are commonly found in the environment. NTM pulmonary infections affect a significant proportion of people with CF worldwide, which may be associated with a more rapid decline in lung function and even death in certain circumstances. Although there are guidelines for the antimicrobial treatment of NTM lung disease, there is no specific evidence from studies of people with CF to inform recommendations for their treatment. It is not clear which antibiotic regimen may be the most effective in the treatment of people with CF. This is an update of a previous review.

OBJECTIVES: To compare antibiotic treatment to no antibiotic treatment, or to compare different combinations of antibiotic treatment, for suppressing or eradicating non-tuberculous mycobacteria (NTM) lung infections in people with cystic fibrosis (CF).

SEARCH METHODS: We searched Cochrane's Cystic Fibrosis Trials Register, online databases (MEDLINE, Embase and PubMed) and online trials registries (www.

CLINICALTRIALS: gov and the World Health Organization International Clinical Trials Registry). We also searched the reference lists of included studies and relevant reviews. The date of the last search was 14 October 2024.

ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs with a parallel design; non-randomised studies of interventions (NRSIs) with the following designs: instrumental variables; regression discontinuity; interrupted time series; difference-in-differences and fixed-effect designs. These should have compared antibiotic treatment to no antibiotic treatment, or different combinations of antibiotic treatment, in people with CF of any age with NTM pulmonary infection.

OUTCOMES: We aimed to assess the critical outcomes of microbiological clearance of NTM in sputum, quality of life, adverse events, lung function and pulmonary exacerbations. Further, we planned to assess important outcomes of mortality, nutritional parameters, hospitalisations and use of additional oral antibiotics.

RISK OF BIAS: We planned to use the recommended Cochrane tools for RCTs or NRSIs. These were not suitable for the included study, so we assessed the risk of bias using a tool for case series developed by the Joanna Briggs Institute.

SYNTHESIS METHODS: We were only able to report the limited results from the single included study narratively. We assessed the certainty of the results using GRADE.

INCLUDED STUDIES: Due to a lack of studies of the types planned, we were only able to include a single retrospective case review, which presented data as the change from baseline for some outcomes. It was conducted in Sweden in 2003 and included 11 participants with CF and NTM infection (three males) aged between 10 and 36 years. The study identified the specific cystic fibrosis transmembrane conductance regulator (CFTR) mutation for 10 participants. All participants were chronically colonised with Pseudomonas aeruginosa; 10 participants had been vaccinated with the Bacillus Calmette-Guérin vaccine. Antibiotic selection differed amongst participants and was determined according to in vitro susceptibility testing. Antibiotics included isoniazid, ethambutol, rifampicin (or rifabutin), amikacin, clarithromycin, ciprofloxacin, streptomycin and clofazimine. Of note, at the start of the study, isoniazid was the standard treatment for NTM, and three participants received this drug; however, investigators stated that following severe adverse effects, the drug was excluded in the latter part of the 1980s. Investigators reported data for lung function, weight and adverse events one year before NTM diagnosis, at baseline, at completion of therapy and at the latest follow-up (ranging from one to 14 years). Treatment was considered effective if NTM was cleared and cultures remained negative throughout treatment; it was considered to have failed if there were continued or sporadic positive cultures.

SYNTHESIS OF RESULTS: We graded all the evidence as very low and are very uncertain of the effects of the different antibiotic regimens on any of the outcomes reported. The study reported that in 10/11 participants, microbiological cultures turned negative. They also stated that five participants reported adverse events; three reported photosensitivity to ciprofloxacin, while each of the following events was reported by one of the five participants: impaired hearing, convulsions, neuropathy and lupus erythematous. There was no consistent effect on lung function. Investigators reported that forced expiratory volume in one second increased by between 1% predicted and 46% predicted in six participants, decreased between 2% predicted and 31% predicted in four participants and remained the same in one participant. They also reported that forced vital capacity increased in eight participants by between 3% predicted and 53% predicted, and decreased in three participants by between 4% predicted and 21% predicted. Two participants died as a result of progression of CF respiratory disease two years after completion of therapy. A further participant died of gastrointestinal bleeding and renal insufficiency eight years after lung transplant which followed clearance of NTM infection (negative NTM cultures were maintained until death). Eight participants gained weight (range 3.30 kg to 14.00 kg), while three participants lost weight (range -0.90 kg to -6.00 kg). Investigators additionally reported body mass index values in three participants, which decreased minimally in two participants and increased slightly in the third participant.

AUTHORS' CONCLUSIONS: The very low-certainty evidence identified in this review suggests that antimicrobial treatment may lead to sputum clearance of NTM in people with CF, but may result in variable clinical response in terms of lung function. Very low-certainty evidence also suggests that adverse events may be common, necessitating close monitoring. This review highlights the need for larger, more standardised studies in order to make meaningful comparisons between treatment regimens. Although microbiological clearance seems feasible, studies should be powered to detect relevant clinical outcomes as well.

FUNDING: Cochrane CF received funding from the Cystic Fibrosis Foundation for a series of reviews on NTM, of which the update of this review is one.

REGISTRATION: The protocol for this updated version of the review was registered at PROSPERO in November 2023.

PMID:40145528 | DOI:10.1002/14651858.CD016039

JHLT Open. 2024 Jan 17;3:100055. doi: 10.1016/j.jhlto.2024.100055. eCollection 2024 Feb.

ABSTRACT

BACKGROUND: Blood transfusion is often necessary during and after lung transplantation surgery. Point-of-care guided bleeding strategies, such as rotational thromboelastometry (ROTEM), can reduce blood transfusion in cardiovascular surgery. This study aimed to assess the effect of ROTEM-guided bleeding management on the need for allogenic blood transfusion, prohemostatic medication, and clinical outcomes in lung transplantation patients.

METHODS: This single-center retrospective cohort study compared patients receiving bilateral lung transplantation between 2010-2014 and 2017-2020. The first cohort was treated with a clinically guided bleeding strategy and the second cohort with a ROTEM-guided bleeding strategy. Multivariable regression analyses were performed to determine the effects on primary outcomes.

RESULTS: A total of 167 (66 clinically guided vs 101 ROTEM-guided) patients were included for analysis. Baseline, intraoperative, and postoperative characteristics were mostly similar, but differed regarding the number of patients with cystic fibrosis, use of cardiopulmonary bypass, and surgical technique. The ROTEM-guided group received significantly less median red blood cells (7 [3; 13] vs 4 [1; 9] units, p < 0.01), platelet concentrate (2 [0; 3] vs 0 [0; 2] units, p = 0.01), and plasma volume (2,310 [1,320; 3,960] vs 800 [0; 1,600] ml, p < 0.01). In multivariable regression analysis, implementation of the ROTEM strategy only remained significantly associated with a decreased use of plasma volume. Cardiopulmonary bypass significantly increased allogenic blood transfusion needs. Moreover, more prothrombin complex concentrate, fibrinogen concentrate, and less tranexamic acid were used in the ROTEM-guided group.

CONCLUSIONS: ROTEM-guided bleeding management reduces plasma transfusion in bilateral lung transplant surgery and cardiopulmonary bypass seems to increase transfusion needs.

PMID:40145117 | PMC:PMC11935446 | DOI:10.1016/j.jhlto.2024.100055

JHLT Open. 2024 Nov 20;7:100182. doi: 10.1016/j.jhlto.2024.100182. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: As life expectancy following lung transplantation (LT) improves, vulnerability to glucocorticoid-induced osteoporotic fractures is increased. Our institution offers LT recipients protocolized antiresorptive therapy, with zoledronic acid (ZA) used first line.

METHODS: Adults who underwent LT from January 2012 to December 2018 and survived at least 6 months were retrospectively studied. Coprimary outcomes were incidence, prevalence, and predictors of osteoporotic fractures and major osteoporotic fractures post-LT.

RESULTS: Four hundred and five LT recipients (41% female, median age 59 years) had a median follow-up of 4.9 years (interquartile range 3.4-6.7). Osteoporotic fracture prevalence was 12% (n = 49) pre-LT and 15% (n = 60) post-LT. Major osteoporotic fracture post-LT occurred in 11% (n = 45). Antiresorptive therapy was received by 47% pre- and 89% post-LT. On multivariate analysis, risk factors for osteoporotic fracture were pre-LT osteoporotic fracture (hazard ratio (HR) 2.32 (95% confidence interval (CI) 1.09-4.96)), female sex (HR 2.08 (95% CI 1.09-3.94)), glucocorticoid use pre-LT (HR 2.08 (95% CI 1.09-3.99)), and time (months) to first ZA infusion post-LT (HR 1.04 (95% CI 1.01-1.06)). Risk factors for major osteoporotic fracture were pre-LT osteoporotic fracture, female sex, age, and time to first ZA infusion.

CONCLUSION: LT recipients receiving protocolized antiresorptive treatment post-LT had a low incidence of osteoporotic fracture.

PMID:40144833 | PMC:PMC11935502 | DOI:10.1016/j.jhlto.2024.100182

JHLT Open. 2025 Jan 17;7:100210. doi: 10.1016/j.jhlto.2025.100210. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) for people with CF (PwCF) after lung transplantation (LTx) has been restrained due to uncertainties regarding efficacy and drug interactions. Given the persistence of extrapulmonary symptoms post-LTx, this prospective study aims to investigate the benefits and safety of ETI for PwCF post-LTx.

METHODS: Between Nov 2022-Nov 2023 ETI was offered to PwCF post-LTx with at least one F508del mutation in 3 Dutch LTx centers. PwCF were considered eligible if they had either a BMI ≤ 19 kg/m², chronic rhinosinusitis (CRS), uncontrolled diabetes or gastrointestinal (GI) symptoms. BMI, HbA1c, SNOT-22 score, GI Symptom Tracker, CF Questionnaire-Revised (CFQ-R), FEV1, creatinine, changes in calcineurin inhibitor (CNI) doses and levels were compared between baseline and 3 months follow-up.

RESULTS: Fifty-five PwCF post-LTx were included, of whom 5 were excluded because of ETI discontinuation due to side effects, within 3 month follow-up. Three months results showed a decrease in SNOT-22 score (p< 0.001) and GI symptoms (all 4, p< 0.05), an increase in BMI (p= 0.012) and CFQ-R (6 domains, p< 0.05). Median CNI daily dose had to be reduced from 6 to 4 mg (p< 0.001), to maintain stable CNI trough levels. Creatinine increased from 110 (87-141) to 115 (92-125) umol/L (p= 0.002).

CONCLUSION: ETI for PwCF post-LTx shows favorable effects on CRS, GI symptoms, and quality of life, but not on BMI and HbA1c. Due to its high cost, careful consideration and further studies are required. Monitoring renal function and CNI trough levels is recommended.

PMID:40144832 | PMC:PMC11935345 | DOI:10.1016/j.jhlto.2025.100210

JHLT Open. 2025 Jan 15;7:100212. doi: 10.1016/j.jhlto.2025.100212. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: Concomitant liver and lung transplant (ConLi-LTx) may be indicated for select pediatric patients with cystic fibrosis (CF). This study aims to analyze pre-transplant predictors and post-transplant outcomes of ConLi-LTx and lung transplant (LTx) only in pediatric patients with cystic fibrosis.

METHODS: The ISHLT International Thoracic Organ Transplant Registry was queried for patients <18 years old with CF who underwent ConLi-LTx and LTx-only from 1994-June 2018. Data were propensity matched to LTx-only controls and analyzed with Fisher's exact, Wilcoxon rank sum tests, Kaplan-Meier methods, and Cox proportional hazards where appropriate.

RESULTS: We identified 18 ConLi-LTx who were compared to 72 LTx-only cases. No significant differences were identified in patient demographics, resting oxygen requirement prior to transplant, or six-minute walking distance at time of listing. Interestingly, ConLi-LTx patients demonstrated significantly improved overall (p=0.0220) and BOS-free survival (p=0.0167).

CONCLUSIONS: There were no differences in pre-transplant predictors of simultaneous liver and lung transplantation in pediatric patients with cystic fibrosis compared to those who received LTx-only. The noted survival benefits of ConLi-LTx remains uncertain, as patients who underwent simultaneous transplant are likely well-selected as candidates for such an extensive procedure, and we hypothesize that the liver may play a role in immunologic benefit. Further research is warranted regarding pre-transplant characteristics of pediatric cystic fibrosis patients who may be considered for concomitant liver with lung transplant.

PMID:40144828 | PMC:PMC11935521 | DOI:10.1016/j.jhlto.2025.100212

JHLT Open. 2024 Oct 26;7:100171. doi: 10.1016/j.jhlto.2024.100171. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive condition leading to progressive lung disease and often necessitating lung transplantation. Historically, CF has been one of the leading indications for lung transplants in the United States. The advent of CF transmembrane conductance regulator (CFTR) modulators, particularly elexacaftor-tezacaftor-ivacaftor (ETI), has significantly improved clinical outcomes for people with CF (pwCF), offering potential alterations in disease progression and transplantation needs.

METHODS: Data on lung transplants performed in the United States since 1988 were retrieved from the Organ Procurement & Transplantation Network. Custom reports were generated to compare the number of lung transplants and waitlist additions before and after ETI approval in 2019. The analysis focused on trends from 2009-2019 (pre-ETI) and 2021-2023 (post-ETI).

RESULTS: The average annual lung transplants for CF decreased significantly from 243 (2009-2019) to 56.7 (2021-2023) post-ETI approval. Similarly, the average number of pwCF added to the lung transplant waitlist per year dropped from 295 to 55.6. Despite an overall increase in lung transplants and waitlist additions in the United States, the proportion involving pwCF has markedly declined post-ETI.

CONCLUSIONS: The introduction of ETI has dramatically reduced the need for lung transplants among pwCF, reflecting significant improvements in lung function and disease management. These findings underscore the transformative impact of CFTR modulators like ETI on the natural history of CF, highlighting the importance of continued advancements in precision medicine for genetic disorders. Future studies should investigate long-term outcomes and sustained trends in lung transplantation needs among pwCF.

PMID:40144821 | PMC:PMC11935324 | DOI:10.1016/j.jhlto.2024.100171

Front Pharmacol. 2025 Mar 12;16:1531514. doi: 10.3389/fphar.2025.1531514. eCollection 2025.

ABSTRACT

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) has demonstrated significant efficacy in enhancing clinical outcomes for patients with cystic fibrosis (CF). Despite this, comprehensive post-marketing assessments of its adverse drug events (ADEs) remain insufficient. This study aims to analyze the ADEs associated with ETI using the U.S. FDA Adverse Event Reporting System (FAERS).

METHODS: We conducted a pharmacovigilance analysis utilizing FAERS data from Q4 2019 to Q3 2024. Reports of ADEs related to ETI were extracted, and disproportionality analyses-including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS)-were employed to evaluate signal strength. Additionally, a time-to-onset (TTO) analysis was performed.

RESULTS: A total of 28,366 ETI-related ADEs were identified, spanning 27 organ systems. We identified 322 positive signals, with signals consistent with the drug label including headache (702 cases, ROR 2.75), infective pulmonary exacerbation of CF (691 cases, ROR 384.24), rash (538 cases, ROR 2.72), and cough (507 cases, ROR 3.79). Unexpected signals were also noted, such as anxiety (494 cases, ROR 4.16), depression (364 cases, ROR 4.59), insomnia (281 cases ROR 2.83), nephrolithiasis (79 cases, ROR 3.63) and perinatal depression (4 cases, ROR 13.59). The TTO analysis indicated that the median onset of ADEs was 70 days, with 37.08% occurring within the first month. Subgroup analyses revealed that females exhibited a higher reporting rank for mental disorder and constipation, whereas in males, they were insomnia, abdominal pain, and nasopharyngitis.

CONCLUSION: This study highlights both recognized and unexpected ADEs associated with ETI, underscoring the necessity for ongoing monitoring, particularly concerning psychiatric conditions. The subgroup analysis suggests a need for personalized treatment strategies to optimize patient care.

PMID:40144660 | PMC:PMC11937142 | DOI:10.3389/fphar.2025.1531514

iScience. 2025 Feb 21;28(3):111979. doi: 10.1016/j.isci.2025.111979. eCollection 2025 Mar 21.

ABSTRACT

Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X is the second-most common CF-causing variant, and it does not respond to current CFTR modulator drugs. Our study explores the use of adenine base editing to edit G542X to a non-CF-causing variant, G542R, and recover CFTR function. Using base editor engineered virus-like particles (BE-eVLPs) in patient-derived intestinal organoids, we achieved ∼2% G542X-to-G542R editing efficiency and restored CFTR-mediated chloride transport to ∼6.4% of wild-type levels, independent of modulator treatment, and with no bystander edits. This proof-of-principle study demonstrates the potential of base editing to rescue G542X and provides a foundation for future in - vivo applications.

PMID:40144632 | PMC:PMC11938077 | DOI:10.1016/j.isci.2025.111979

JHLT Open. 2023 Oct 20;2:100011. doi: 10.1016/j.jhlto.2023.100011. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Acute exacerbations of interstitial lung disease (AE-ILD) cause severe respiratory failure, and mortality is high despite treatment. Lung transplantation is an effective therapy for late-stage interstitial lung disease (ILD), but prior studies on post-transplant outcomes for patients trandsplanted in AE-ILD are conflicting.

METHODS: We performed a retrospective evaluation of all first-time lung transplant recipients for ILD performed at our institution between May 1, 2005, and April 1, 2019. Patients were stratified according to a published consensus definition into AE-ILD recipients, other inpatients, or outpatients. One-year survival was compared with a Cox proportional hazards model. Subset analysis was performed on those with idiopathic pulmonary fibrosis (IPF). Patients were also assessed for survival free of long-term chronic lung allograft dysfunction (CLAD).

RESULTS: We identified 717 first-time lung transplant ILD recipients: 41 inpatients in AE-ILD, 31 other inpatients, and 645 outpatients. One-year survival was 93% for AE-ILD recipients, 61% for other inpatient recipients, and 82% for outpatient recipients. Those transplanted in AE-ILD had a lower hazard of death or retransplantation compared to other inpatients (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.04-0.56) and outpatients (HR 0.29, CI 0.09-1.00). Results were similar among the subset of patients with IPF, but differences were not significant. For those transplanted during AE-ILD, rates of CLAD were not significantly different compared to other inpatients (HR 1.34, CI 0.51-3.54) or to outpatients (HR 1.05, CI 0.52-2.13).

CONCLUSIONS: With careful selection, patients in AE-ILD can be transplanted and have acceptable 1-year outcomes without increased risk of long-term graft dysfunction.

PMID:40144010 | PMC:PMC11935389 | DOI:10.1016/j.jhlto.2023.100011

JHLT Open. 2024 May 28;5:100113. doi: 10.1016/j.jhlto.2024.100113. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Cytomegalovirus (CMV) is the most common viral infection among lung transplant recipients and is associated with chronic lung allograft dysfunction. There is a need for better therapeutics as well as biomarkers to enable effective stratification of CMV seropositive patient risk for developing CMV DNAemia to inform prophylaxis duration.

METHODS: CMV-specific immunoglobulin G (IgG) binding and functional responses were evaluated in a discovery cohort of longitudinal plasma samples from 51 CMV seropositive human lung transplant recipients, collected as part of the clinical trials in organ transplantation (CTOT)-20 and CTOT-22 consortium studies. Pre-transplant plasma from an additional 43 CMV seropositive lung transplant recipients was evaluated as a validation cohort.

RESULTS: In the discovery cohort with longitudinal samples, pre-transplant plasma IgG binding to CMV surface glycoproteins glycoprotein H (gH)/glycoprotein L (gL), gH/gL/glycoprotein O (gO), and pentameric complex, as well as neutralization of CMV in epithelial cells, is associated with increased risk of CMV DNAemia post-prophylaxis. However, these results were not confirmed by the validation cohort.

CONCLUSIONS: While quantification of pre-transplant CMV-specific antibody responses showed association with DNAemia in the discovery cohort, additional clinical variables and/or known risk factors for CMV, such as patient CMV-specific T-cell responses, may need to be considered in combination with humoral immunity to effectively stratify risk of CMV DNAemia.

PMID:40143922 | PMC:PMC11935385 | DOI:10.1016/j.jhlto.2024.100113

JHLT Open. 2024 May 10;5:100107. doi: 10.1016/j.jhlto.2024.100107. eCollection 2024 Aug.

ABSTRACT

Higher body mass index (BMI) increases the risk of developing primary graft dysfunction (PGD) after lung transplantation; whether BMI is associated with decreased survival after PGD is unknown. We utilized the Lung Transplant Outcomes Group cohort of 1,538 subjects from 2011-2018. We evaluated the association between preoperative BMI and graft survival among subjects with severe PGD using Cox proportional hazards models with linear splines. Models were stratified by center and adjusted for sex, age, Lung Allocation Score, and diagnosis. PGD developed in 383 subjects. Among subjects with PGD, low BMI was associated with increased mortality while high BMI was not associated with differential mortality, compared to normal BMI. Results were similar for 90-day and 1-year survival. While high BMI increases the risk of developing PGD, it does not appear to be associated with survival after PGD. Future work should focus on PGD prevention rather than PGD management in patients with obesity.

PMID:40143915 | PMC:PMC11935391 | DOI:10.1016/j.jhlto.2024.100107

JHLT Open. 2024 Apr 24;5:100096. doi: 10.1016/j.jhlto.2024.100096. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) has increased over time. While 1-year and overall survival have been reported to be similar with non-ECMO transplant recipients, there are limited data on major adverse cardiovascular and cerebrovascular events (MACCE) and clinically relevant bleeding (CRB) events. In this study, we sought to evaluate the incidence of perioperative MACCE and CRB in lung transplant recipients who underwent ECMO BTT.

METHODS: Using the National Inpatient Sample from 2008-2019, we identified 5,254 lung transplant recipients who either received or did not require pretransplant ECMO. Perioperative MACCE and CRB were compared between the 2 cohorts.

RESULTS: Patients with ECMO BTT had a higher incidence of MACCE compared to non-ECMO patients (35% vs 13.3%, p < 0.0001) and CRB (34.5% vs 12.9%, p < 0.0001). Recipients of pretransplant ECMO for double lung transplant (n = 158) were more likely to have perioperative MACCE and CRB as opposed to patients without pretransplant ECMO (n = 3,584) (adjusted odds ratio 2.69, p < 0.0001; 95% confidence interval 1.86-3.80). The ECMO BTT cohort was notably younger with less cardiac comorbidities and higher diagnoses of cystic fibrosis and interstitial lung disease.

CONCLUSIONS: Our data indicate that lung transplant recipients who required ECMO BTT are at significantly higher risk of MACCE and bleeding events despite being younger with less comorbidities as opposed to those who did not require ECMO.

PMID:40143905 | PMC:PMC11935470 | DOI:10.1016/j.jhlto.2024.100096

JHLT Open. 2024 Jul 1;5:100122. doi: 10.1016/j.jhlto.2024.100122. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Predicting post-transplant (PT) survival in lung allocation remains an elusive goal. We analyzed the impact of donor factors on PT survival and how these relationships vary among transplant recipients.

METHODS: We studied primary bilateral lung transplant recipients (n = 7,609) from the US Scientific Registry of Transplant Recipients (19 February 2015-1 February 2020). Main and interaction effects were evaluated and adjusted across candidate age, sex, and diagnosis. Models predicting PT survival were compared to the PT Composite Allocation Score model (PT-CAS): (1) Cox regression donor multivariable model (COX), (2) COX + PT-CAS, (3) random forest model (RF), and (4) RF + PT-CAS. Model discrimination and calibration measures were compared.

RESULTS: Interactions between donor and recipient factors emerged by age: lower survival for donation after circulatory death organs for recipients aged 55 to 69 years, donor smoking for recipients aged 30 to 54 and 70+, Hispanic donor for recipients <30, non-Hispanic Black donor for recipients aged 30+; sex: cytomegalovirus mismatch for males; diagnosis: higher donor recipient weight ratio for diagnosis group C (e.g., cystic fibrosis), donor diabetes for diagnosis group D (e.g., idiopathic pulmonary fibrosis). COX and RF models performed similarly to PT-CAS; however, the combined COX + PT-CAS model had improved discrimination (1-year area under the receiver operator characteristic curve [AUC] PT-CAS 0.609 vs 1-year AUC COX + PT-CAS 0.626) and improved calibration across a broader range of predicted risk.

CONCLUSIONS: The influence of donor factors on recipient PT survival differed by age, sex, and diagnosis. The addition of donor factors to existing models predicting PT survival led to only modest improvement in prediction accuracy. Future efforts may focus on optimizing matching strategies to improve donor utilization.

PMID:40143895 | PMC:PMC11935449 | DOI:10.1016/j.jhlto.2024.100122